Ontology highlight
ABSTRACT:
PROVIDER: PRJNA634157 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11821839.fastq.gz | Fastqsanger.gz | |||
| SRR11821840.fastq.gz | Fastqsanger.gz | |||
| SRR11821841.fastq.gz | Fastqsanger.gz | |||
| SRR11821842.fastq.gz | Fastqsanger.gz | |||
| SRR11821843.fastq.gz | Fastqsanger.gz |
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Project description:The Alzheimer's Disease and Parkinson's Disease risk locus Fyn kinase is implicated in protein pathophysiology and NF-κB microglia inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Gene expression analyses reveal reduction in neuroprotective genes, and elevated inflammatory cytokines Il-1β, IL-12 and TNF-α and genes associated with oxidative stress. These phenotypes correlate with microglia activation in the larval brain. Chemical inhibition demonstrates dopaminergic neuron loss is dependent on Fyn and NF-κB/Caspase 1 signaling. We identify Stat3 activation as a novel downstream effector of Fyn signaling that acts synergistically with NF-κB in dopaminergic neuron degeneration. These results show Fyn drives neurodegeneration through NF-κB inflammatory signaling and Stat3 pathways. Activation of Stat3 provides a potential link from Fyn to mitochondrial dysfunction associated with dopaminergic neuron loss.
2024-11-25 | GSE271955 | GEO
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
2015-02-01 | GSE63092 | GEO
Project description:To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analysis and identified 366 genes with altered expression in four unique tamoxifen resistant (TamR) cell lines vs the parental tamoxifen sensitive MCF7/S0.5 cell line. Most of these genes were funcationally linked to cell proliferation, death and control gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF7/S0.5 cells resulted in reduced sensitivity to tamoxifen, demonstrating growth and survival promoting function of FYN in MCF7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and CDc 25A, suggesting that FYN, by activation of of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N = 47) and the other with early disease (N = 76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.
2016-04-10 | GSE67916 | GEO
Project description:microRNA-7-5p (miR-7-5p) is an established tumor suppressor in multiple cancer types and inhibits growth and invasion by suppressing expression and activity of the epidermal growth factor receptor (EGFR) signaling pathway. While melanoma is not typically driven by EGFR signaling, expression of miR-7-5p is reduced in metastatic tumors compared to primary melanoma. Here, we investigated the biological and clinical significance of miR-7-5p in melanoma. Our results showed that augmenting miR-7-5p expression in vitro markedly reduced tumor cell viability, colony formation and induced cell cycle arrest. Furthermore, ectopic expression of miR-7-5p reduced migration and invasion of melanoma cells in vitro and reduced melanoma lung colonizationmetastasis in vivo. To investigate the mechanism underlying this effect, we used cDNA microarray analysis to identify a subset of putative miR-7-5p target genes associated with melanoma and metastasis. Of these, we confirmed nuclear factor kappa B (NF-κB) subunit RelA, as a novel direct target of miR-7-5p in melanoma cells, such that miR-7-5p suppresses NF-κB activity to decrease expression of canonical NF-κB target genes, including IL-1a, IL-6 and IL-8. Importantly, the effects of miR-7-5p on melanoma cell growth, cell cycle, migration and invasion were recapitulated by RelA knockdown. Finally, analysis of gene array datasets from multiple melanoma patient cohorts revealed an association between elevated RelA expression and poor survival, further emphasizing the clinical significance of RelA and its downstream signaling effectors.. Taken together, our data suggest that miR-7-5p replacement therapy might have clinical utility in melanoma to inhibit the metastatic process, in part through its inactivation of RelA/NF-kB signaling. Total RNA was extracted from WM266-4 cells transfected with miR-NC or miR-7-5p precursor molecules (30 nM) for 24 h, using Qiazol reagent (Qiagen).
2016-02-10 | E-GEOD-77196 | biostudies-arrayexpress
Project description:Fyn kinase has been implicated in multiple behavioral responses to ethanol and in the regulation of myelin gene expression. Here we tested whether Fyn kinase modulated basal or ethanol-responsive expression of genes regulated by acute ethanol in brain regions of the mesolimbocortical dopamine pathway. Using expression profiling, we sought to define Fyn-dependent gene networks underlying ethanol behavioral traits; with emphasis on ethanol-induced loss of righting reflex (LORR) due to the reproducible association of Fyn kinase genotype with this behavioral phenotype (Miyakawa et al., 1997, Boehm et al., 2003, Yaka et al., 2003, Boehm et al., 2004b). Our expression profiling and bioinformatics results suggest multiple Fyn-related mechanisms, especially those affecting a network of myelin-related gene expression within the medial PFC, as contributing to the sedative-hypnotic properties of ethanol. Variation in the expression of these Fyn-dependent gene networks may be critical molecular endophenotypes affecting the behavioral level of response to acute ethanol, and subsequently, the long-term risk for alcohol use disorders. Adult male control (B6129SF2/J) and Fyn-kinase null (B6;129S7-Fyntm1Sor/J) mice were treated with saline or ethanol (3.0 g/kg x 4 hours) and brain regions harvested by microdissection for total RNA expression profiling by Affymetrix microarrays. Samples were randomly assigned to batch groups prior to total RNA extraction, cRNA synthesis and hybridization. Each microarray represents a pooling of 3 animals and 3 arrays were analyzed per treatment group for a total of 12 arrays per brain region. Statistical and bioinformatics analysis was used to identify Fyn-dependent effects on basal and ethanol-responsive gene expression, with a particular focus on myelin-related gene expression. This series of samples includes medial prefrontal cortex (PFC).
2014-08-31 | E-GEOD-49028 | biostudies-arrayexpress
Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.
2023-11-02 | GSE243814 | GEO
Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.
2023-11-02 | GSE236680 | GEO